The HO-1/CO system is a significant part of the defense against the damage inflicted by a variety of stress conditions mediated by heavy metals, reactive oxygen species, lipopolysaccharide (LPS) and other inflammatory processes, thereby playing a pivotal role in the regulation of the cytoprotective and anti-inflammatory responses.
CO gas administered at low doses (250 ppm) for restricted period of times has been shown to reproduce (restore) many of the beneficial effects of HO-1 in models of cardiovascular dysfunction, pulmonary hypertension, and inflammatory conditions such as sepsis and inflammatory bowel disease.
Because of the interest in HO-1/CO therapeutic potential, compounds that liberate controlled amounts of CO (CO-releasing molecules, CO-RMs) to biological systems have been developed and demonstrated to exert a wide array of pharmacological effects related to CO release. The vast majority of pharmacologically active CO-RMs described in the literature are metal carbonyls containing either Ru, Fe, Mn, Co and Mo.
The transcription factor Nrf2 is a crucial initiator of the cellular stress response as it co-ordinates the expression of several antioxidant and detoxification genes that repair damage and restore cellular homeostasis. As part of this inducible response, heme oxygenase-1 (HO-1) plays a prominent role by utilizing heme to produce CO, biliverdin/bilirubin and iron, important signaling and protective molecules against oxidative stress and inflammation.
Many chemicals have been identified to act as Nrf2/HO-1 activators and among them several naturally-derived compounds having an α,β-unsaturated carbonyl functionality, including curcumin, the first chemical found to increase HO-1 expression, and chalcones. The list of Nrf2/HO-1 activators has now grown to include several hundred compounds. Because of their mechanism of action, Nrf2/HO-1 activators require time to mount the cellular stress response, resulting in a delayed, albeit essential, beneficial effect.
The synthesis of a molecule possessing both the ability to rapidly release CO and simultaneously stimulate a longer-lasting Nrf2-dependent protective proteome, offers significant therapeutic advantages compared to CO-RMs or Nrf2 activating agents alone in diseases where these pathways are crucial for tissue protection, and there is therefore a need for such molecules.
Zhu et al. (J. Organomet. Chem. 2006, 691, 485-490) discloses compound [Co2(CO6)(μH2CCH2O)—]2(CO)2, however referring only to its use in mixed metal linked alkyne bridged butterfly clusters containing C2Co2R2, with applications in the synthesis of polymeric materials.
WO 2012/076696 discloses curcumin derivatives bound to a CO-releasing molecule. The inventors of the present invention have however shown that these molecules do not release carbon monoxide. This lack of CO-release results in molecules that do not exhibit the wide array of beneficial therapeutic effects related to the activation of HO-1 by CO.
WO 2008/003953 also describes CO-releasing molecules of formula (I): Mn(CO)4XY wherein X and Y are monodentate ligands, or taken together form a bidentate ligand, for the therapeutic delivery of CO to humans and animals. More specifically, WO 2008/003953 discloses CO-releasing compound 364, wherein X represents O(O)CCH2CH2C(O)OH and Y represents Br. However, this molecule demonstrated poor CO-releasing abilities.
Unexpectedly, it has been discovered that hybrid molecules comprising a fumarate moiety and a CO-releasing molecule (CORM) are capable of rapidly liberating CO and activating the Nrf2/HO-1 pathway, resulting in a dual activation of the inflammatory defenses in cells and an improved therapeutic efficacy.
The present invention concerns both compounds with one CORM moiety (mono-CORM compounds) and with two CORM moieties (bi-CORM compounds). The inventors have discovered that both types of molecules have improved therapeutic activities. Moreover, it has been observed that mono-CORM molecules release very quickly high levels of CO, thus exerting a “burst effect”. On the other hand, bi-CORM compounds release higher levels of CO (in particular because of the presence of a second CORM moiety), but less rapidly and over a longer period of time. Therefore, mono-CORM compounds of the invention will be used when a “burst effect” is sought for, while bi-CORM compounds of the invention will be used when a sustained release over a long period of time is more appropriate for the patient or with regard to the disease or condition to be treated.
The present invention therefore concerns hybrid fumarate-carbon monoxide releasing molecules (fumarate-CORM), their pharmaceutically acceptable salts, hydrates and solvates, of formula (I):
wherein:A represents:                a single bond, or        —Z-Q-, where:                    Q represents O, S or NR2, where R2 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl or (C1-C6)alkyl-(C3-C6)heterocyclyl, —(C3-C14)cycloalkyl, or R2 and Z are connected to form a (C3-C6)heterocyclyl,            Z represents —(C1-C6)alkyl-, —(C2-C6)alkenyl-, -aryl-, -heteroaryl-, —(C2-C6)alkynyl-, —(C3-C6)heterocyclyl-, —(C3-C14)cycloalkyl, —(C1-C6)alkyl-R3—(C1-C6)alkyl-, —(C2-C6)alkenyl-R3—(C1-C6)alkyl-, —(C1-C6)alkyl-R3—(C2-C6)alkenyl-, —(C2-C6)alkenyl-R3—(C2-C6)alkenyl-, —(C1-C6)alkyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkenyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkynyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkynyl-R3—(C1-C6)alkyl-, —(C2-C6)alkynyl-R3—(C2-C6)alkenyl-, —(C1-C6)alkyl-OCO—, or —CH2—(CHOR3)CH2O—(C1-C6)alkyl-, where R3 represents aryl, heteroaryl, (C3-C6)heterocyclyl, or (C3-C14)cycloalkyl,CORM represents a carbonyl metal complex chosen from among:                        Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Rh, Co, Ru, Mn, Mo, V or Fe, preferably Co, Ru or Mn, and        n is an integer chosen so that the metal M has no free valency,preferably, CORM represents a carbonyl metal complex chosen from among:        Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,and R1 represents:        -Q′-Y, where                    Q′ represents O, S or NR5, where R5 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl or (C1-C6)alkyl-(C3-C8)heterocyclyl, —(C3-C14)cycloalkyl,            Y represents H, —(C1-C6)alkyl, —(C2-C6)alkenyl, -aryl, -heteroaryl, —(C2-C6)alkynyl, —(C3-C8)heterocyclyl, —(C3-C14)cycloalkyl, —(C1-C6)alkyl-R6—(C1-C6)alkyl, —(C2-C6)alkenyl-R6—(C1-C6)alkyl, —(C1-C6)alkyl-R6—(C2-C6)alkenyl, —(C2-C6)alkenyl-R6—(C2-C6)alkenyl, —(C1-C6)alkyl-R6—(C2-C6)alkynyl, —(C2-C6)alkenyl-R7—(C2-C6)alkynyl, —(C2-C6)alkynyl-R6—(C2-C6)alkynyl, —(C2-C6)alkynyl-R6—(C1-C6)alkyl, —(C2-C6)alkynyl-R6—(C2-C6)alkenyl, (C1-C6)alkyl-R6, —(C2-C6)alkenyl-R6, —(C2-C6)alkynyl-R6, where R6 represents aryl, heteroaryl, (C3-C8)heterocyclyl, or (C3-C14)cycloalkyl, —CH2(CHOR6)CH2—OR7, where R7 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, (C1-C6)alkyl-(C3-C6)heterocyclyl, (C1-C6)alkyl-(C3-C14)cycloalkyl,                        or,        A′-CORM′ where A′ and CORM′ are as defined respectively for A and CORM.        
Advantageously, CORM is chosen from among:                Mn(CO)5,        
more advantageously from among:
even more advantageously from among

The present invention preferably concerns hybrid fumarate-carbon monoxide releasing molecules (fumarate-CORM), their pharmaceutically acceptable salts, hydrates and solvates, of formula (I) above, wherein:
A represents:
                a single bond, or        —Z-Q-, where:                    Q represents O, S or NR2, where R2 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl or (C1-C6)alkyl-(C3-C8)heterocyclyl, —(C3-C14)cycloalkyl, or R2 and Z are connected to form a (C3-C8)heterocyclyl,            Z represents —(C1-C6)alkyl-, —(C2-C6)alkenyl-, -aryl-, -heteroaryl-, —(C2-C6)alkynyl-, —(C3-C6)heterocyclyl-, —(C3-C14)cycloalkyl, —(C1-C6)alkyl-R3—(C1-C6)alkyl-, —(C2-C6)alkenyl-R3—(C1-C6)alkyl-, —(C1-C6)alkyl-R3—(C2-C6)alkenyl-, —(C2-C6)alkenyl-R3—(C2-C6)alkenyl-, —(C1-C6)alkyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkenyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkynyl-R3—(C2-C6)alkynyl-, —(C2-C6)alkynyl-R3—(C1-C6)alkyl-, —(C2-C6)alkynyl-R3—(C2-C6)alkenyl-, —(C1-C6)alkyl-OCO—, or —CH2—(CHOR3)CH2O—(C1-C6)alkyl-, where R3 represents aryl, heteroaryl, (C3-C8)heterocyclyl, or (C3-C14)cycloalkyl,R1 represents:                        -Q′-Y, where                    Q′ represents O, S or NR5, where R5 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl or (C1-C6)alkyl-(C3-C8)heterocyclyl, —(C3-C14)cycloalkyl,            Y represents H, —(C1-C6)alkyl, —(C2-C6)alkenyl, -aryl, -heteroaryl, —(C2-C6)alkynyl, —(C3-C8)heterocyclyl, —(C3-C14)cycloalkyl, —(C1-C6)alkyl-R6—(C1-C6)alkyl, —(C2-C6)alkenyl-R6—(C1-C6)alkyl, —(C1-C6)alkyl-R6—(C2-C6)alkenyl, —(C2-C6)alkenyl-R6—(C2-C6)alkenyl, —(C1-C6)alkyl-R6—(C2-C6)alkynyl, —(C2-C6)alkenyl-R7—(C2-C6)alkynyl, —(C2-C6)alkynyl-R6—(C2-C6)alkynyl, —(C2-C6)alkynyl-R6—(C1-C6)alkyl, —(C2-C6)alkynyl-R6—(C2-C6)alkenyl, (C1-C6)alkyl-R6, —(C2-C6)alkenyl-R6, —(C2-C6)alkynyl-R6, where R6 represents aryl, heteroaryl, (C3-C8)heterocyclyl, or (C3-C14)cycloalkyl, —CH2(CHOR6)CH2—OR7, where R7 represents H, (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, (C1-C6)alkyl-(C3-C6)heterocyclyl, (C1-C6)alkyl-(C3-C14)cycloalkyl,                        or,        A′-CORM′ where A′ and CORM′ are as defined respectively for A and CORM, and, when R1 represents -Q′-Y, CORM represents a carbonyl metal complex chosen from among:        Mn(CO)5,        
where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,M represents Rh, Co, Ru, Mn, Mo, V or Fe, preferably Co, Ru or Mn andn is an integer, chosen so that the metal M has no free valency;and when R1 represents A′-CORM′, CORM represents a carbonyl metal complex chosen from among:                Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Rh, Co, Ru, Mn, Mo, V or Fe, preferably Fe, Co, Ru or Mn and        n is an integer, chosen so that the metal M has no free valency;        preferably CORM represents a carbonyl metal complex chosen from among:        Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Rh, Ru, Mn, Mo, V or Fe, preferably Fe, Ru or Mn, and        n is an integer, chosen so that the metal M has no free valency;        even more preferably CORM represents a carbonyl metal complex chosen from among:        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Fe or Mn, and        n is an integer chosen so that the metal M has no free valency.        
The present invention even more preferably relates to hybrid fumarate-carbon monoxide releasing molecules (fumarate-CORM), their pharmaceutically acceptable salts, hydrates and solvates, of formula (Ia):
wherein A, CORM and -Q′-Y are as defined for formula (I).
In the case where CORM represents a carbonyl metal complex of formula:
M represents Rh, Co, Ru, Mn, Mo, V or Fe, preferably Co, Ru or Mn, andn is an integer chosen so that the metal M has no free valency, more preferablyn is an integer from 1 to 4, chosen so that the metal M has no free valency. In particular, when M represents Rh, n represents 2; when M represents Co, n represents 2; when M represents Ru, n represents 2; when M represents Mn, n represents 3; when M represents Mo, n represents 3; when M represents V; n represents 4; when M represents Fe, n represents 3.
Advantageously, Q represents O or NR2, preferably O and R2 represents H or (C1-C6)alkyl.
Advantageously, Z represents —(C1-C6)alkyl-, —(C2-C6)alkenyl- or —(C3-C8)heterocyclyl-, —(C1-C6)alkyl-R3—(C1-C6)alkyl-, —(C2-C6)alkenyl-R3—(C1-C6)alkyl- and R3 represents heteroaryl or (C3-C8)heterocyclyl.
Advantageously, Q represents O, S or NR2, where R2 represents H, (C1-C6)alkyl and Z represents —(C1-C6)alkyl-, —(C2-C6)alkenyl-, —(C3-C6)heterocyclyl-, —(C1-C6)alkyl-R3—(C1-C6)alkyl-, —(C2-C6)alkenyl-R3—(C1-C6)alkyl-, where R3 represents heteroaryl or (C3-C8)heterocyclyl.
More advantageously, Z represents:

Advantageously, CORM is chosen from among:
more advantageously from among
even more advantageously from among

Advantageously, Q′ is O or NR5, preferably O.
Advantageously, Y is chosen from among H; —(C1-C6)alkyl, —(C2-C6)alkenyl; -aryl, -heteroaryl, —(C2-C6)alkynyl, —(C3-C6)heterocyclyl; —(C3-C8)cycloalkyl or —(C1-C6)alkyl-aryl.
According to a first embodiment, the invention concerns a hybrid fumarate-carbon monoxide releasing molecule (fumarate-CO—RM), in which the fumarate moiety is substituted on one side by a CO-releasing carbonyl complex and on the other side by an acid, an ester, a thioester or an amide, of formula (Ia):
wherein A, CORM and -Q′-Y are as defined for formula (I).
Unexpectedly, it has been found that the compounds of formula (Ia) are capable of releasing CO at a fast rate. For example, compound A of the examples below, illustrative of the compounds of formula (Ia), is capable of releasing CO with a half-life of around 38 minutes under the in vitro conditions described in the examples, which is a fast rate in the sense of the present invention. The compounds of formula (Ia) are therefore advantageous for a relatively fast biological activity. Moreover, experiments demonstrate that the compounds of the invention comprising only one CORM group are potent activators of Nrf2 and inducers of HO-1 protein expression, and are more effective than dimethylfumarate.
Some advantageous compounds according to this first embodiment have formula (Ia1):
wherein:M represents Mn(CO)4 or Ru(CO)3Cl, andQ, Q′, W, Z and Y are as defined for formula (I).
Advantageously, in the compounds of formula (Ia1), Z—W is —CH2—CH2—NR7—,
where R7 represents (C1-C3)alkyl.
Advantageously, Q is O or NR2, preferably O.
Advantageously, Q′ is O or NR5, preferably O.
Advantageously, Y represents H, —(C1-C6)alkyl or —(C2-C6)alkenyl.
Some other advantageous compounds according to this first embodiment have formula (Ia2):
wherein:Q′ and Y are as defined for formula (I).
Advantageously, Y is H, —(C1-C6)alkyl or —(C2-C6)alkenyl and Q′ represents O.
Some further advantageous compounds according to this first embodiment have formula (Ia3):
wherein:Q, Q′, Y and Z are as defined for formula (I).
Advantageously, Y is H, —(C1-C6)alkyl or —(C2-C6)alkenyl, Q′ is O, and Q and Z are as defined for formula (I). More advantageously, Q-Z is the side chain of an amino-acid such as serine, cysteine, tyrosine or lysine.
Further advantageous compounds according to this first embodiment have formula (Ia4):
wherein:Mx(CO)y represents Co2(CO)6 or Co4(CO)10,Q′, Q, Y and Z are as defined for formula (I).
Advantageously, Y is H, —(C1-C6)alkyl or —(C2-C6)alkenyl, Q′ is O, and Q and Z are as defined for formula (I).
More advantageously, Q is O and Z is —(C1-C6)alkyl, preferably (C1-C3)alkyl.
In a second embodiment, the invention concerns a hybrid fumarate-carbon monoxide releasing molecule (fumarate-CO-RM) in which the fumarate moiety is substituted on both sides by a CO-releasing carbonyl complex.
These bimetallic compounds have been found to release a higher amount of CO compared to the monometallic over a long period of time and are therefore advantageous for a sustained biological activity over time. For example, compound B of the examples below, illustrative of the compounds of formula (Ic) described thereafter, is capable of releasing CO over 480 minutes under the in vitro conditions described in the examples, which is a long period of time in the sense of the present invention.
In some compounds according to this second embodiment, the hybrid fumarate-carbon monoxide releasing molecule is substituted on one side by one CO-releasing carbonyl complex and on the other side by a different CO-releasing carbonyl complex, according to formula (Ib):
wherein A-CORM and A′-CORM′ are as defined above or below for formula (I).
Advantageously, CORM and CORM′ are respectively
wherein M is Mn(CO)4 or Ru(CO)3Cl.
Advantageously, in the compounds of formula (Ib), A is Q-Z—W wherein Z—W is —CH2—CH2—NR7—,
where R7 represents (C1-C3)alkyl and A′ is Q′-Z′, wherein Z′ is —(C1-C6)alkyl, preferably (C1-C3)alkyl. Advantageously, Q is O or NR2, preferably O and Q′ is O or NR2, preferably O.
Advantageously, the compounds according to the second embodiment have formula (Ic), wherein the fumarate moiety is substituted on both sides by the same CO-releasing carbonyl complex:
wherein A-CORM is as defined for the compounds of formula (I).
In this embodiment, CORM preferably represents a carbonyl metal complex chosen from among:                Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Rh, Co, Ru, Mn, Mo, V or Fe, preferably Fe, Co, Ru or Mn and        n is an integer chosen so that the metal M has no free valency;        preferably CORM represents a carbonyl metal complex chosen from among:        Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Rh, Ru, Mn, Mo, V or Fe, preferably Fe, Ru or Mn, and        n is an integer chosen so that the metal M has no free valency;        even more preferably CORM represents a carbonyl metal complex chosen from among:        Mn(CO)5,        
                where W represents O or NR4, where R4 represents —(C1-C6)alkyl-,        L represents an ionic ligand such as halogen, or a counter-ion such as BF4 or PF6,        M represents Fe or Mn, and        n is an integer chosen so that the metal M has no free valency.        
Some advantageous compounds of formula (Ic) have formula (Ic1):
wherein:M represents Mn(CO)4 or Ru(CO)3Cl, andQ and Z are as defined for formula (I).
Advantageously, in the compounds of formula (Ic1), Z—W is —CH2—CH2—NR7—,
where R7 represents (C1-C3)alkyl
Advantageously, Q is O or NR2, preferably O.
Some other advantageous compounds of formula (Ic) have formula (Ic2):

Some further advantageous compounds of formula (Ic) have formula (Ic3):
wherein:Q and Z are as defined for formula (I).
Advantageously, Q-Z is the side chain of an amino-acid such as serine, cysteine, tyrosine or lysine.
Further advantageous compounds of formula (Ic) have formula (Ic4):
wherein:Mx(CO)y represents Co2(CO)6 or Co4(CO)10, preferably Co4(CO)10,Q and Z are as defined for formula (I).More advantageously, Q is O and Z is —(C1-C6)alkyl, preferably (C1-C3)alkyl.Advantageously, the compound of formula (I) is chosen from among:
In a particular embodiment, the compound of formula (I) is:

The invention also concerns a pharmaceutical composition comprising at least one compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, as defined previously and at least one pharmaceutically acceptable excipient.
The pharmaceutical compositions of the invention are advantageously suitable for administration via oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal route. The pharmaceutical compositions of the invention may also be administered by inhalation, for example by means of an aerosol. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals or to humans.
When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle and other conventional excipients known to those skilled in the art.
The compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day. The daily administered dose is advantageously comprises between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.
The present invention further concerns a compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition comprising at least one compound of formula (I), a salt, solvate or hydrate thereof, for use as a drug.
The present invention further concerns at least one compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition comprising at least one compound of formula (I), a salt, solvate or hydrate thereof, for use in the treatment of cardiovascular or inflammatory diseases.
The present invention further concerns the use of at least one compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for use in the treatment of cardiovascular or inflammatory diseases.
The present invention further concerns a method for treating cardiovascular or inflammatory diseases, comprising the administration of at least one compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, or of a pharmaceutical composition comprising at least one compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, to a person in need thereof.
Inflammatory and cardiovascular diseases according to the present invention include for example myocardial ischemia and heart diseases, rheumatoid arthritis, acute and chronic skin wound (wound healing), inflammatory bowel disease, post-operative ileus, brain ischemia, psoriasis, diabetes, diabetic nephropathy, metabolic syndrome, sickle-cell disease, neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, neuropathic pain, hypertension, pulmonary arterial hypertension, septicemia, septic or endotoxic shock, hemorrhagic shock, multiple sclerosis, cancer and chronic obstructive pulmonary disease. Preferred inflammatory and cardiovascular diseases according to the present invention are skin wound (wound healing), brain and cardiac ischemia, psoriasis, diabetes, multiple sclerosis, cancer and chronic obstructive pulmonary disease. The present invention further concerns a process for preparing the compounds of formula (I), their salts, hydrates or solvates.
The compounds of formula (I) can be obtained according to two methods.
Method (a):
Step (1): The diacyl chloride, bromide, fluoride or di-activated ester of fumaric acid or the monoacyl chloride, bromide, fluoride or mono-activated ester of a mono-ester, mono-amide or mono-thioester of fumaric acid is esterified with a compound of formula (II) chosen from among:
wherein Z and Q are as defined above.
Alternatively, fumaric acid or the mono-ester of fumaric acid may be alkylated with a compound of formula (III) chosen from among:
wherein Z and Q are as defined above and Hal represents a leaving group such as halogen or sulfonate, such as trifuoromethane-sulfonate.Step (2): the compound obtained in step (1) is reacted with a suitable carbonyl metal complex of formula L1L2Mx(CO)y where x is 1 or 2 and y is 1 to 10, L1 and L2 represent each a monodentate ligand or L1L2 represents a bidentate ligand to yield after optional deprotection the compound of formula (I).
The invention therefore concerns a process for the synthesis of a compound of formula (I) comprising the reaction of a fumaric acid derivative of formula (IV):
                wherein:        X1 represents A-R8, A-CORM, A′-CORM′ or Q′-Y as defined for formula (I), and        R8 represents a group chosen from among:        
with a carbonyl metal complex of formula L1L2Mx(CO)y where x is 1 or 2 and y is 1 to 10, L1 and L2 represent each a monodentate ligand or L1L2 represents a bidentate ligand.Method (b):
The diacyl chloride, bromide, fluoride or di-activated ester of fumaric acid or the monoacyl chloride, bromide, fluoride or mono-activated ester of a mono-ester, mono-amide or mono-thioester of fumaric acid is esterified with a compound of formula H-A-CORM. Alternatively, fumaric acid or the mono-ester of fumaric acid may be alkylated with a compound of formula Hal-A-CORM, wherein A is as defined above and Hal represents a leaving group such as halogen or sulfonate, such as trifuoromethane-sulfonate.
The invention therefore also concerns a process for the synthesis of a compound of formula (I) comprising the reaction of a fumaric acid derivative of formula (V):
                wherein:        X1 represents Cl, F, Br or an ester, advantageously an activated ester,        X2 represents Cl, F, Br or an ester, advantageously an activated ester, A-CORM, A′-CORM′ or Q′-Y as defined for formula (I),with a compound of formula H-A-CORM wherein A-CORM is as defined for formula (I),        or,the reaction of a compound of formula (I) wherein X1 and/or X2 represent OH with a compound of formula Hal-A-CORM where Hal represents a leaving group, such as halogen or sulfonate, for example a trifuoromethane-sulfonate.        
In the sense of the present invention, the term “leaving group” refers to a chemical group which can be easily replaced with a nucleophile during a nucleophile substitution reaction.
In the sense of the present invention, the expression “activated ester” is intended to designate an ester that enhances the reactivity of the carbonyl group(s) of fumaric acid. Such activated esters can be prepared before the reaction or generated in situ according to well-known procedures.
Examples of reagents usable for preparing the activated esters include coupling agents, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), hexafluorophosphate 2H benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), tetrafluoroborate 2-(IH-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (TBTU), hexafluorophosphate O (7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HATU) or (benzotriazol-1-yloxy)tripyrrolodinophosphonium hexafluorophosphate (PyBOP); optionally associated with an auxiliary coupling, such as N-hydroxy-succinimide (NHS), N-hydroxy-benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole (HOOBt), I-hydroxy-7-azabenzotriazole (HAt) or N-hydroxysylfosuccinimide (sulfo NHS).
When present, functional groups liable to interfere with the desired reaction, for example heteroatoms, such as N or O, may be protected to avoid undesirable reactions during synthetic procedures.
The person skilled in the art is liable to determine if protecting groups are necessary. Suitable protecting groups are known in the art and are for example disclosed in Greene, “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981).
The monoesters of fumaric acid, that is, the compounds of formula (II), wherein X1 represents Q′-Y, can be prepared by esterification, amidation or thioesterification of fumaric acid or a derivative thereof with a compound of formula H-Q′-Y, or by alkylation of fumaric acid with a compound of formula Hal-Y, wherein Hal is a leaving group such as Br, Cl, I or OSO2CF3 and Y is as defined above under conventional conditions.
The compounds of formula (V) wherein X1 represents A-CORM can be prepared by reacting fumaric acid with a compound of formula H-A-CORM or Hal-A-CORM according to method (b) described above, and if required transformation of the carboxylic acid into an acyl chloride, bromide, fluoride or activated ester.
The compounds of formula (Ic) can be obtained in a one-step procedure by reacting the diacyl chloride of fumaric acid with two equivalents of a compound of formula H-A-CORM or two equivalents of a compound chosen from among:
followed by the reaction with at least two equivalents of a carbonyl metal complex of formula L1L2Mx(CO)y where x is 1 or 2 and y is 1 to 10, L1 and L2 represent each a monodentate ligand or L1L2 represents a bidentate ligand with respect to the amount of the fumarate ester.
The compound of formula (Ia2) and (1c2) can be obtained by reacting the monoacyl chloride of a fumarate ester or the diacyl chloride of fumaric acid with an appropriate amount of an anionic manganese carbonyl complex such as Na+[Mn(CO)5]−.
The conditions for preparing the compounds of formula H-A-CORM or the compounds of formula (I) according to method (a) involve methods and procedures known in the art.